Role of Testosterone in Modulating Tau Pathogenesis in Females

睾酮在调节女性 Tau 发病机制中的作用

基本信息

批准号：
10685501
负责人：
Xu Chen
金额：
$ 56.64万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685501
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease risk Androgen Receptor Androgens Animals Anti-Inflammatory Agents Apolipoprotein E Apolipoproteins Astrocytes Biology Brain Cerebrospinal Fluid Clinical Clinical Data Cognitive deficits Collaborations Compensation Data Deposition Development Disease Disease Pathway Estrogens Female Functional disorder Gene Expression Genetic Goals Gonadal Steroid Hormones Hormones Human Impaired cognition Inflammation Intervention Knock-in Knock-in Mouse Knowledge Link Literature Mediating Metabolism Microglia Modeling Molecular Mus Neurodegenerative Disorders Neurons Neurosecretory Systems Operative Surgical Procedures Outcome Ovariectomy Pathogenesis Pathologic Pathology Pathway interactions Physiological Progesterone Publishing Receptor Signaling Regulation Reporting Reproductive Biology Research Research Personnel Risk Reduction Role Sex Differences Signal Transduction Stanolone Supplementation Synapses Tauopathies Testosterone Therapeutic Transgenic Mice Translational Research Woman Work brain cell capsule cell type clinical application cognitive function conditional knockout effective intervention effective therapy genetic manipulation high risk improved insight male men mouse model neuroimaging neuroinflammation neuronal survival neuroprotection novel pharmacologic precision medicine preclinical study programs protective effect receptor-mediated signaling reproductive senescence response sex single nucleus RNA-sequencing subcutaneous tau Proteins tau aggregation tau-1 therapeutic target transcriptome transcriptomics

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) and other tau-mediated neurodegenerative diseases are characterized by aggregation and spread of pathological tau protein in the brain. Despite decades of research, effective interventions to these diseases are still lacking. It is well-evidenced that women typically show greater tau pathology than men on the AD trajectory; yet the reason for such sex differences is poorly understood. A better understanding of the mechanisms underlying the greater tau deposition in women can benefit all by informing causal pathways of disease and therapeutic targets and strategies that are optimal for each sex. Clinical evidence suggests that low testosterone levels correlate with poorer cognitive function and greater risk for AD. In particular, a recent study in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) revealed that women with lower testosterone tend to have higher levels of phosphorylated tau (p-tau) in cerebrospinal fluid (CSF), particularly among ApoE4 carriers. This suggest that lower testosterone levels that typically characterize women may predispose them to pathological tau, and contribute to sex differences observed in AD. To take these correlative findings to the necessary next step, our overall objectives are to establish the causal relationship between testosterone and tau in females, to explore the clinical applicability of testosterone therapy, and to elucidate the underlying molecular mechanisms. Given testosterone’s anti-inflammatory actions and neuroprotective effects on AD-related outcomes, we hypothesize that pharmacological induction of high testosterone protects against pathological tau accumulation and spread, diminishes neuroinflammation and ameliorates cognitive deficits associated with tau pathogenesis, particularly in ApoE4 females. Based on published preclinical studies on testosterone, we further hypothesize that the protective effects of testosterone are linked to androgen receptor signaling in astrocytes and neurons, leading to enhanced neuronal survival, synaptic integrity and reduces neuroinflammation. This project is a new direction in our research program: In collaboration with experts on reproductive biology and gene expression, we will combine our expertise in tau biology, sex hormones and transcriptomics to determine how testosterone modulates tau pathogenesis in a sex-specific manner. We will: 1) Determine how increase of testosterone levels affects tau pathogenesis in female tau transgenic mouse models with human ApoE4/E3 knock-in; 2) Elucidate the molecular mechanism underlying the protective effects of testosterone in ApoE4 females by single nucleus RNA sequencing, and determining the involvement of neuronal and astrocytic androgen receptor signaling. This project aims to close critical gaps in our understanding of mechanisms underlying sex differences in tau pathophysiology, and provide novel insights into the influence of androgen on molecular mechanisms central to AD pathogenesis. Results from the proposed research will address NIA strategic goals: understand the progression of Alzheimer’s (A), and identify potential therapeutic targets for the development of precision medicine treatments for men and women (D).

项目摘要阿尔茨海默氏病（AD）和其他TAU介导的神经退行性疾病的特征是聚集和病理tau蛋白在大脑中的传播。尽管进行了数十年的研究，但对这些的有效干预措施疾病仍然缺乏。很好地证明，女性通常比男性在广告轨迹；然而，这种性别差异的原因很众所周知。更好地理解女性大tau沉积的基础机制可以通过告知因果途径而受益疾病和治疗目标和最佳性别的策略。临床证据表明低睾丸激素水平与较差的认知功能和AD风险更大相关。特别是，最近的研究阿尔茨海默氏病神经影像学倡议（ADNI）表明，患有睾丸激素较低的女性倾向于在脑脊液（CSF）中，尤其是在APOE4载体中，较高水平的磷酸化tau（P-TAU）。这表明通常表征女性的睾丸激素水平较低，可能使她们偏爱病理tau，并导致在AD中观察到的性别差异。为了将这些相关发现带到必要的下一步，我们的总体目标是建立女性睾丸激素和tau之间的因果关系，以探索睾丸激素治疗的临床适用性，并阐明了基本的分子机制。给出睾丸激素对广告相关结果的抗炎作用和神经保护作用，我们假设高睾丸激素的药物诱导可防止病理tau的积累和扩散，减少神经炎症并改善与tau发病机理相关的认知缺陷，特别是在apoe4女性中。基于公开的关于睾丸激素的临床前研究，我们进一步假设睾丸激素的保护作用与星形胶质细胞和神经元中的雄激素受体信号传导有关，导致增强的神经元存活，突触完整性并降低神经炎症。这个项目是一个新的方向我们的研究计划：与复制生物学和基因表达的专家合作，我们将结合我们在tau生物学，性恐怖和转录组学方面的专业知识，以确定睾丸激素如何调节tau 以性别特异性方式发生发病机理。我们将：1）确定睾丸激素水平的增加如何影响tau 女性tau转基因小鼠模型的发病机理，具有人类APOE4/E3敲进； 2）阐明分子单核RNA对睾丸激素在APOE4女性中受保护作用的机制测序并确定神经元和星形细胞雄激素受体信号的参与。这项目旨在弥合我们对tau性别差异的机制的理解病理生理学，并提供有关雄激素对核心机制的影响的新见解 AD发病机理。拟议研究的结果将解决NIA战略目标：了解阿尔茨海默氏症（a）的进展，并确定精确发展的潜在治疗靶标男性和女性的医学治疗（D）。